BOTOX® The Real Facts

BOTOX® The Real Facts

David H. Hammett, M.D.Neurology

March 26, 2012

4540 Trenholm Road4540 Trenholm RoadColumbia, SC 29206Columbia, SC 29206(803) 790-4700(803) 790-4700

4540 Trenholm Road4540 Trenholm RoadColumbia, SC 29206Columbia, SC 29206(803) 790-4700(803) 790-4700

Introduction to BOTOX®

How does BOTOX® Work?

BOTOX® in the Treatment of Blepharospasm

BOTOX® in the Treatment of Cervical Dystonia

BOTOX® for Severe Primary Axillary Hyperhidrosis

BOTOX® in the Treatment of Spasticity

BOTOX® in the Treatment of Chronic Migraine

Important Information About BOTOX®

Presentation OverviewPresentation Overview

HistoryHistoryHistoryHistory

In the 1820s, the biological basis for food In the 1820s, the biological basis for food poisoning was not understood. poisoning was not understood.

Studies began on a batch of improperly Studies began on a batch of improperly prepared sausages responsible for the prepared sausages responsible for the death of several dozen people in death of several dozen people in Germany. Germany.

First suggestion that there was something First suggestion that there was something in the spoiled sausages that brought in the spoiled sausages that brought on the disease.on the disease.

These experiments led to a better These experiments led to a better understanding of the neurological understanding of the neurological symptoms of food-borne botulism symptoms of food-borne botulism (ptosis, dysphagia, muscle weakness, (ptosis, dysphagia, muscle weakness, and, if left untreated, paralysis and and, if left untreated, paralysis and respiratory failure). respiratory failure). 

HistoryHistoryHistoryHistory

More than 70 years later, Dr. More than 70 years later, Dr. Emile Pierre van Ermengem Emile Pierre van Ermengem of Belgium was asked to of Belgium was asked to investigate an outbreak of investigate an outbreak of botulism following a funeral botulism following a funeral dinner where three people dinner where three people died and 23 were paralyzed. died and 23 were paralyzed.

Van Ermengem was able to make Van Ermengem was able to make a connection between a connection between botulism and a spore-forming botulism and a spore-forming bacterium he named Bacillus bacterium he named Bacillus botulinus (now known as botulinus (now known as Clostridium botulinumClostridium botulinum). Many ). Many scientific studies followed, scientific studies followed, and seven strains of and seven strains of botulinum toxin were botulinum toxin were eventually identified (A-G). eventually identified (A-G).

HistoryHistoryHistoryHistory

In 1978, an Opthalmologist (Dr.Scott) In 1978, an Opthalmologist (Dr.Scott) received approval to inject minute received approval to inject minute amounts of botulinum toxin into amounts of botulinum toxin into human volunteers. human volunteers.

In the early 1980s, he published a In the early 1980s, he published a number of studies including a 1981 number of studies including a 1981 paper in the Transactions of the paper in the Transactions of the American Ophthalmological Society American Ophthalmological Society that asserted botulinum toxin that asserted botulinum toxin “appears to be a safe and useful “appears to be a safe and useful therapy for strabismus.” therapy for strabismus.”

Additional research showed the drug’s Additional research showed the drug’s benefits went beyond benefits went beyond ophthalmology, providing patients ophthalmology, providing patients with temporary relief from facial with temporary relief from facial spasms, neck and shoulder spasms, spasms, neck and shoulder spasms, even vocal cord spasms. even vocal cord spasms.

HistoryHistoryHistoryHistory

In 1988, drugmaker Allergan In 1988, drugmaker Allergan acquired the rights to acquired the rights to distribute Scott’s batch of distribute Scott’s batch of botulinum toxin type A (or botulinum toxin type A (or Oculinum, as it was then Oculinum, as it was then known) and a year later, the known) and a year later, the FDA approved botulinum FDA approved botulinum toxin type A for the treatment toxin type A for the treatment of both strabismus and of both strabismus and blepharospasm. blepharospasm.

Shortly thereafter, Allergan Shortly thereafter, Allergan acquired Scott’s company acquired Scott’s company and changed the drug’s and changed the drug’s name to the compact, catchy name to the compact, catchy “Botox.” “Botox.”

1950s Scientists discover that botulinum toxin canreduce muscle spasms.

1960s/1970s Studies explore botulinum toxin as a treatment for strabismus (crossed eyes).

1988 Allergan researches other medical uses of botulinum toxin.

1989 Allergan introduces BOTOXBOTOX®, the first botulinumtoxin approved by the FDA to treat blepharospasm(eyelid spasms) and strabismus.

2000 FDA approves BOTOX® for cervical dystonia

1950s Scientists discover that botulinum toxin canreduce muscle spasms.

1960s/1970s Studies explore botulinum toxin as a treatment for strabismus (crossed eyes).

1988 Allergan researches other medical uses of botulinum toxin.

1989 Allergan introduces BOTOXBOTOX®, the first botulinumtoxin approved by the FDA to treat blepharospasm(eyelid spasms) and strabismus.

2000 FDA approves BOTOX® for cervical dystonia

Timeline – Development and FDATimeline – Development and FDATimeline – Development and FDATimeline – Development and FDA

2002 FDA approves BOTOX® CosmeticBOTOX® Cosmetic, (sameformulation as BOTOX®) for moderate to severe frown lines between the brow.

2004 FDA approves BOTOX® for severe underarm sweating

2009 20-year anniversary of BOTOX®.

2010 FDA approves BOTOX® for upper limb spasticity.

2010 BOTOX® is approved by the FDA specifically for the prevention of headaches in adults with Chronic

Migraine (15 or more days each month with headache lasting 4 or more hours each day)

2011 FDA approval for neurogenic urinary incontinence

2002 FDA approves BOTOX® CosmeticBOTOX® Cosmetic, (sameformulation as BOTOX®) for moderate to severe frown lines between the brow.

2004 FDA approves BOTOX® for severe underarm sweating

2009 20-year anniversary of BOTOX®.

2010 FDA approves BOTOX® for upper limb spasticity.

2010 BOTOX® is approved by the FDA specifically for the prevention of headaches in adults with Chronic

Migraine (15 or more days each month with headache lasting 4 or more hours each day)

2011 FDA approval for neurogenic urinary incontinence

Timeline – Development and FDATimeline – Development and FDATimeline – Development and FDATimeline – Development and FDA

Glabellar Frown LinesGlabellar Frown LinesGlabellar Frown LinesGlabellar Frown Lines

Glabellar frown lines Glabellar frown lines are the most are the most common reason for common reason for cosmetic injection cosmetic injection of botulinum toxin.of botulinum toxin.

BOTOX® (onabotulinumtoxinA) for Chronic Migraine Patients: A Prophylactic Treatment Paradigm

BOTOX® (onabotulinumtoxinA) for Chronic Migraine Patients: A Prophylactic Treatment Paradigm

Please see Indication, Important Limitations, and Important Safety Information, including Boxed Warning, throughout this deck.

IndicationIndication

BOTOX® (onabotulinumtoxinA) for injection is indicated for the prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer).

Important limitations

Safety and effectiveness have not been established for the prophylaxis of episodic migraine (14 headache days or fewer per month) in seven placebo-controlled studies.  

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IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNINGIMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING

Distant Spread of Toxin Effect

Postmarketing reports indicate that the effects of BOTOX® and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening, and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity, but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have an underlying condition that would predispose them to these symptoms. In unapproved uses, including spasticity in children, and in approved indications, cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and at lower doses.

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Please see additional Important Safety Information throughout this deck.

Diagnostic Criteria for Chronic MigraineDiagnostic Criteria for Chronic Migraine

Chronic Migraine is a defined condition1-3

15 or more headache days per month

• Headaches lasting 4 hours per day or more

• At least 8 headache days classified as migraine days

• With or without medication overuse

What are migraine characteristics1?

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1. Headache Classification Committee; Olesen J et al. Cephalalgia. 2004;24:9-160.2. Headache Classification Committee; Olesen J et al. Cephalalgia. 2006;26:742-746.3. Lipton RB. Headache. 2011;51(S2):77·83.

Please see Important Safety Information, including Boxed Warning, on slides 14-20. Please see Important Safety Information, including Boxed Warning, throughout this deck.

Case Study: EmilyCase Study: Emily

Patient History: • 43-year-old woman is seen for a

main complaint of headache

• She has had headaches since her teens

• She reports 8 migraine attacks per month, each lasting 2–3 days

• She has migraine features (nausea, photophobia, and phonophobia) on all headache days

• She has tried multiple preventive medications

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Please see Important Safety Information, including Boxed Warning, on slides 14-20.Please see Important Safety Information, including Boxed Warning, throughout this deck.

Case Studies do not involve actual patients

Study Design of Two Phase 3 Studies of Chronic Migraine Patients1,2

Study Design of Two Phase 3 Studies of Chronic Migraine Patients1,2

• Large clinical program of Chronic Migraine sufferers (1384 patients)

Double-Blind PhaseDouble-Blind Phase Open-Label PhaseOpen-Label Phase

Primary Time Point

BOTOX® vs Placebo All Patients on BOTOX®

Phone Interview Treatment

Baseline Randomization

We

ek

s

12 32 36 40 44 48 524 8 16 20 28 56-4 Day0 24

BOTOX® vs Placebo (saline)

BOTOX® vs Placebo (saline)

BOTOX® BOTOX® BOTOX®

1. Aurora SK et al. Cephalalgia. 2010;30:793-803. 2. Diener HC et al. Cephalalgia. 2010;30:804-814.

• Headache symptoms and medications were recorded in a daily telephone diary

1 2 3 4 5

Please see Important Safety Information, including Boxed Warning, throughout this deck.

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Efficacy of BOTOX® at Week 24 for Study 1 and Study 2 Efficacy of BOTOX® at Week 24 for Study 1 and Study 2

52 BOTOX® (onabotulinumtoxinA) Prescribing Information. Allergan, Inc., 2011. BOTOX® (onabotulinumtoxinA) Prescribing Information. Allergan, Inc., 2011.

*Significantly different from placebo (p≤0.05)

Please see Important Safety Information, including Boxed Warning, throughout this deck.

Adverse Reactions Reported by 2% of Patients Treated With BOTOX (More Frequent Than Placebo) in Two Chronic Migraine Double-Blind, Placebo-Controlled Clinical Trials1

Adverse Reactions Reported by 2% of Patients Treated With BOTOX (More Frequent Than Placebo) in Two Chronic Migraine Double-Blind, Placebo-Controlled Clinical Trials1

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*Aurora et al 2011 reported n=38 (5.5%); 2.2% of the incidences of muscular weakness were facial paresis.2 1. BOTOX® (onabotulinumtoxinA) Prescribing Information. Allergan, Inc., 2011. 2. Aurora SK et al. Headache. 2011;51:1358-1373.

Severe worsening of migraine requiring hospitalization occurred in approximately 1% of patients treated with BOTOX ®

in Study 1 and Study 2, usually within the first week after treatment, compared to 0.3% of placebo-treated patients.

Please see Important Safety Information, including Boxed Warning, throughout this deck.

Discontinuation RatesDiscontinuation Rates

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*The most frequent adverse events leading to discontinuation in the BOTOX® group were neck pain, headache, worsening migraine, muscular weakness, and eyelid ptosis.

BOTOX® (onabotulinumtoxinA) Prescribing Information. Allergan, Inc., 2011. BOTOX® (onabotulinumtoxinA) Prescribing Information. Allergan, Inc., 2011.

Please see Adverse Reactions table on slides 12 and 24.

Please see Important Safety Information, including Boxed Warning, throughout this deck.

Injection ParadigmInjection Paradigm

• The phase 3 BOTOX® pivotal studies for Chronic Migraine patients has established a treatment paradigm1

• The patient population, recommended dose, and injection paradigm were established based on 10 years of studies assessing various patient types, muscle groups, and doses2-6

• 155 Units of BOTOX® are administered as 31 fixed-site, fixed-dose injections across 7 specific head/neck muscle areas1

• For each injection site, the injection volume will be 0.1 mL (5 Units)1

• Each muscle has a fixed1:• Total dose • Number of injection sites • Location of injection sites

1. Blumenfeld AM et al. Headache. 2010;50:1406-1418. 2. Mathew NT et al. Headache. 2005;45:293-307. 3. Silberstein SD et al. Mayo Clin Proc. 2005;80:1126-1137. 4. Silberstein SD et al. Headache. 2000;40:445-450. 5. Binder WJ et al. Otolaryngol Head Neck Surg. 2000;6:669-676.6. Freitag FG et al. Headache. 2008;48:201-209.

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Please see Important Safety Information, including Boxed Warning, throughout this deck.

Case Study: Emily’s Response to Treatment 2 Weeks Post-InjectionCase Study: Emily’s Response to Treatment 2 Weeks Post-Injection

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In PREEMPT 1 and 2, the first evaluation was 4 weeks post-injection.

Please see Important Safety Information, including Boxed Warning, throughout this deck.

Case Studies do not involve actual patients

Case Study: Monitoring Emily’s Response to Treatment Case Study: Monitoring Emily’s Response to Treatment

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Please see Important Safety Information, including Boxed Warning, throughout this deck.

Case Studies do not involve actual patients

BOTOX®: The Real Facts Summary

Questions

BOTOX®: The Real Facts Summary

Questions